Keywords
noninvasive prenatal testing - NIPT - cell-free DNA - genetic screening
Identifying pregnancies at increased risk for aneuploidy has been a part of the practice
of maternal–fetal medicine for several decades. Originally, women were identified
based on maternal age alone and given the option of diagnostic testing via chorionic
villus sampling (CVS) or amniocentesis to determine the fetal karyotype. Recently,
maternal serum screening tests, with or without ultrasound findings, were developed
for use in the general obstetrical population to identify at-risk pregnancies.[1]
[2] Since CVS and amniocentesis carry a risk for miscarriage, research has continued
to pursue other means of obtaining the fetal genetic complement. Recently, three separate
multicenter trials of noninvasive prenatal testing (NIPT) showed that analyzing cell-free
DNA in the maternal circulation results in a highly sensitive and specific testing
option for fetal aneuploidy, with 98 to 100% detection rate at < 0.3% false-positive
rate for Down syndrome and 97 to 100% detection rate at < 0.28% false-positive rate
for trisomy 18.[3]
[4]
[5]
[6] The detection rate for trisomy 13 varied more widely across studies, ranging from
79 to 92% with < 1% false-positive rate.[4]
[6]
Advances in prenatal screening for aneuploidy have led to a decrease in invasive testing
and an increase in screening in the at-risk population.[7]
[8] Even women who elect amniocentesis report misgivings about placing their pregnancy
at risk.[9] The high detection rate and low false-positive rate for fetal aneuploidy demonstrated
by NIPT coupled with the lack of risk to the fetus poises this new technology to have
significant impact on invasive testing. We conducted a retrospective study to compare
testing uptake before the introduction of NIPT with testing uptake following its introduction
to determine if NIPT significantly altered clinical practice. This information is
important to demonstrate how new technologies impact patient decisions and the practice
of maternal–fetal medicine.
Materials and Methods
A retrospective review of the prenatal genetic counseling database, which contains
information from all patients having genetic counseling at the University of Texas
Health Maternal-Fetal Medicine Clinics in Houston, was performed. The 4 months before
the availability of NIPT (August 1, 2011, through November 30, 2011) and the 4 months
after an established clinical NIPT protocol (March 1, 2012, through June 30, 2012)
were compared to determine whether the uptake rates for invasive diagnostic testing
had changed. The date of genetic counseling, indication, gestational age, number of
gestations, gravidity, parity, and elected testing were obtained. Only singleton gestations
having genetic counseling for advanced maternal age or positive maternal serum screening,
with or without additional indications, before 22 weeks gestation were identified
for statistical analysis. Patients pregnant with multiple gestations and those presenting
after 22 weeks were not included, as the risks and accuracy of available testing options
are different in these groups. Patients within each study time period were further
divided into those seen before 14 weeks gestational age and those seen between 14
and 22 weeks, as unique screening and diagnostic testing options were available to
each group. Finally, per capita prenatal testing reimbursement was calculated for
each time period to determine whether the introduction of NIPT influenced clinical
practice as measured by reimbursement. A model was created to study reimbursement
in each group based on the distribution of patients within the two groups that were
privately insured, Medicaid insured, or self-pay for the following procedures (first
trimester ultrasound-76801, first trimester screen [FTS]-76813, CVS with ultrasound
guidance-59015/76945, and amniocentesis with ultrasound guidance-59000/76946). Reimbursement
for NIPT or other laboratory charges were not included in the analysis, as these are
not captured by our Maternal-Fetal Medicine clinics. For the patients with private
insurance, procedure reimbursement was calculated based on the average of the rates
of our two largest private insurers (Blue Cross Blue Shield and United Health Care).
The collection of data for research was approved by the Institutional Review Board
of the University of Texas Health Science Center at Houston IRB #HSC-MS-12-0384. The
statistical package employed was SPSS 20 (SPSS Inc, Chicago, IL). Comparison of proportions
was performed by Pearson chi-square test. A p value of < 0.05 was considered statistically significant.
Results
A total of 792 patients received genetic counseling between August 1, 2011 and November
30, 2011. Of those, 459 (58%) were seen before 22 weeks for advanced maternal age
and/or abnormal genetic screen. Of the 838 patients seen between March 1, 2012 and
June 30, 2012, 523 (62.4%) were seen before 22 weeks for advanced maternal age and/or
abnormal genetic screen. Maternal age, gravidity, parity, race, insurance, and gestational
age at the time of genetic counseling was not significantly different (p > 0.05) in the pre- and post-NIPT groups when compared with the same gestational
age subgroup ([Table 1]).
Table 1
Demographic and clinical characteristics of the study groups
|
Clinical characteristics
|
Pre-NIPT
< 14 wk GA
(n = 165)
|
Post-NIPT
< 14 wk GA
(n = 193)
|
Pre-NIPT
14–22 wk GA
(n = 294)
|
Post-NIPT
14–22 wk GA
(n = 330)
|
|
Maternal age (y)
|
37.2
(26.1–43.9)
|
37.2
(23.9–46.2)
|
35.7
(16.7–44.5)
|
36.7
(18.9–46.6)
|
|
Gravidity
|
3
(1–10)
|
3
(1–11)
|
3
(1–9)
|
3
(1–12)
|
|
Parity
|
1
(0–7)
|
1
(0–6)
|
1
(0–7)
|
1
(0–10)
|
|
Race (%)
|
|
African American
|
13.3 (22)
|
14.5 (28)
|
17.0 (50)
|
18.2 (60)
|
|
Asian
|
24.2 (40)
|
20.2 (39)
|
15.6 (46)
|
19.4 (64)
|
|
Caucasian
|
36.4 (60)
|
32.6 (63)
|
23.8 (70)
|
15.8 (52)
|
|
Hispanic
|
24.2 (40)
|
28.0 (54)
|
41.2 (121)
|
43.9 (145)
|
|
Other
|
1.8 (3)
|
2.1 (4)
|
2.4 (7)
|
2.1 (7)
|
|
Insurance (%)
|
|
Medicaid
|
9.1 (15)
|
14.5 (28)
|
45.9 (135)
|
46.4 (153)
|
|
Private
|
85.5 (141)
|
79.3 (153)
|
52.4 (154)
|
48.2 (159)
|
|
Other
|
2.4 (4)
|
2.6 (5)
|
0.7 (2)
|
2.4 (8)
|
|
GA at the time of genetic counseling (wk)
|
12.1 (8.7–13.9)
|
12.2 (10.0–13.9)
|
18.3 (14.4–21.9)
|
18.9 (14.0–21.9)
|
Abbreviations: GA, gestational age; NIPT, noninvasive prenatal testing; wk, weeks,
y, years.
Notes: Values are expressed as percentage (number) or median (range). Data regarding gravidity
and parity were missing for 85 patients. Data regarding race were missing for seven
patients. Data regarding insurance were missing for 25 patients.
Overall, NIPT was chosen by 31.6% of patients who received genetic counseling in the
first trimester and by 17.0% in the second trimester. Before the implementation of
NIPT, 89.1% (n = 147) of patients referred before 14 weeks elected to pursue combined FTS. The uptake
of FTS fell significantly to 59.1% (n = 114) following the introduction of NIPT (p < 0.05; [Fig. 1]). The uptake of invasive genetic testing by first trimester patients was not significantly
different with 20.0% (n = 33) pursuing CVS or amniocentesis before NIPT and a 14.0% (n = 27) uptake following the availability of NIPT (p > 0.05; [Fig. 2]). There was, however, a significant decrease in the uptake of invasive diagnostic
testing for those patients receiving genetic counseling between 14 and 22 weeks with
35.4% (n = 104) of patients before NIPT electing amniocentesis and only 17.9% (n = 59) of patients electing amniocentesis after the availability of NIPT (p < 0.05; [Fig. 3]). Although there was a decrease in the uptake of amniocentesis and an increase in
uptake of NIPT, overall, there was no difference in the number of women choosing no
further genetic testing following genetic counseling after the introduction of NIPT
compared with before its introduction (42.4 vs. 41.4%; p < 0.05). Finally, per capita testing reimbursement was 15.77% less following the
introduction of NIPT ($101.32 vs. $85.34).
Fig. 1 The uptake of FTS for patients receiving genetic counseling at < 14 weeks gestational
age before and after the availability of NIPT. Before the implementation of NIPT,
89.1% (n = 147) of patients referred at < 14 weeks elected to pursue FTS. This uptake fell
significantly to 59.1% (n = 114) following the introduction of NIPT (p < 0.05; *). FTS, first trimester screening; NIPT, noninvasive prenatal testing.
Fig. 2 The uptake of invasive diagnostic testing for patients receiving genetic counseling
at < 14 weeks gestational age before and after the availability of NIPT. The uptake
of invasive genetic testing by first trimester patients was not significantly different
with 20.0% (n = 33) pursuing CVS or amniocentesis before NIPT and a 14.0% (n = 27) uptake following the availability of NIPT (p > 0.05). CVS, chorionic villus sampling; NIPT, noninvasive prenatal testing.
Fig. 3 The uptake of invasive diagnostic testing for patients receiving genetic counseling
between 14 and 22 weeks before and after the availability of NIPT. There was a significant
decrease in the uptake of invasive diagnostic testing for those patients receiving
genetic counseling between 14 and 22 weeks with 35.4% (n = 104) of patients before NIPT electing amniocentesis and only 17.9% (n = 59) of patients electing amniocentesis after the availability of NIPT (p < 0.05; *). NIPT, noninvasive prenatal testing.
Comment
Principal Findings
NIPT has already made an impact on our practice of maternal–fetal medicine by significantly
decreasing the number of second trimester diagnostic tests performed. This finding
was also observed by another group when only women with a positive aneuploidy screening
result were studied.[10] Patients interested in early screening information appear to prefer the higher sensitivity
and specificity of NIPT to combined FTS. Early diagnostic information seekers, however,
appear to remain most comfortable with CVS.
Per capita testing reimbursement fell by almost 16%. It is important to note that
it is our practice to perform an ultrasound for viability at the time of NIPT testing
to ensure that NIPT is indicated. Per capita testing reimbursement could fall even
more sharply in units that have not adopted this practice. For example, if our practice
did not include a viability ultrasound before blood draw for NIPT in the first trimester,
a per capita drop of 35.37% would have occurred ($101.32 vs. $65.48). Maternal-Fetal
Medicine clinics will need to take into consideration decreased uptake of second trimester
diagnostic tests and the utilization of viability ultrasounds when evaluating their
business model.
In contrast with the recent findings of Chetty et al,[10] our study did not identify a decline in women choosing no further genetic testing
following the introduction of NIPT. This may be due to the many differences in the
patient populations studied. Our patients were identified by referrals for genetic
counseling for both advanced maternal age and positive maternal serum screening in
parallel to recent practice guidelines developed jointly by the American College of
Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal-Fetal
Medicine Publications Committee for NIPT.[11] Consequently, our patient population was older. Furthermore, they also had a different
ethnic makeup and payer mix.
Strengths and Weaknesses
The strengths of our study include the evaluation of the immediate impact of this
new genetic screening test in a large number of ethnically diverse patients from a
single urban referral area with a uniform protocol for offering NIPT. The protocol
was in accordance with recently published practice guidelines.[11]
[12] Weaknesses include the fact that the study only evaluates the immediate impact of
the introduction of NIPT. These data would be expected to change with increased knowledge
and education about NIPT by both patients and referring physicians. Finally, there
are regional differences in uptake of prenatal genetic screening and invasive diagnostic
testing. Our results may be different than those found in other regions, as well as
more rural areas, of the country.
Implications for Clinicians
It is imperative that clinicians educate themselves about NIPT, as its introduction
is transforming prenatal testing. Taking a family history and reviewing patient records
to determine that a patient is an appropriate candidate, and pretest counseling to
ensure that patients understand the implication of a positive and negative result
is essential.[12]
Unanswered Questions/Future Research
Our study was not designed to look at how the test performs in our clinical setting,
including investigation of false-positive and false-negative rates. Future studies
will be needed to evaluate test performance outside of a clinical trial. It will also
be important to investigate both patient and provider knowledge and understanding
of NIPT.
Conclusions
NIPT has made an impact on the practice of maternal–fetal medicine by significantly
decreasing the number of second trimester diagnostic tests performed and thus per
capita testing reimbursement.
